ES2431275T3 - An improved procedure for the preparation of acid cilastatin - Google Patents

Abstract

An improved process for the preparation of acidic cilastatin of the formula (I), ** Formula ** comprising the steps of: i) condensing 7-chloro-2 - [[((1S) -2,2-dimethylcyclopropane] carboxamide acid ] -2-heptenoic of the formula (II) ** Formula ** with L-cysteine or L-cysteine hydrochloride monohydrate or L-cysteine hydrobromide monohydrate, in the presence of a base and an alcoholic solvent or aqueous alcoholic solvent, ii ) optionally separating the inorganic salt by filtration and concentrating the filtrate, iii) optionally adding water, iv) adjusting the pH from 2.0 to 4.0, v) extracting the acidic cilastatin with C4-C8 alcohol, and vi) isolating the Acid Cilastatin

Description

An improved procedure for the preparation of acid cilastatin

Field of the Invention

The present invention relates to an improved process for the preparation of acidic cilastatin of the formula (I). The present invention also provides a direct technique of isolating acidic cilastatin from the reaction mixture.

Description of the prior art

Cilastatin sodium is the sodium salt of a derivative of heptenoic acid. Its chemical name is salt

Monosodium acid [R- [R *, S * - (Z)]] - 7 - [(2-amino-2-carboxy ethyl) thio] -2 - [[(2,2-dimethylcyclopropyl) carbonyl] amino] -2heptenoic. It is an amorphous, hygroscopic compound, from dirty white to yellowish white. PRIMAXIN (imipenem and cilastatin) is a formulation of imipenem (an antibiotic thienamicin) and cilastatin sodium.

Imipenem with cilastatin acts as an effective antibiotic for the treatment of infections of various body systems. PRIMAXIN is a powerful broad spectrum antibactericidal agent for intramuscular administration. Imipenem can also be described as a semi-synthetic thienamicin that is administered intravenously or intramuscularly in combination with cilastatin to reduce toxicity. Cilastatin, a renal dipeptidase inhibitor, inhibits the enzymatic degradation of imipenem and increases urinary excretion of the active drug.

Originally cilastatin was described in U.S. Patent No. 5,147,868. This patent also describes various processes for the preparation of cilastatin, particularly example 19A of this patent 20 describes a process for the preparation of cilastatin. According to this example, the condensation of the ethyl ester of 7-chloro-2-oxoheptanoic acid (I) with (S) -2,2-dimethylcyclopropanecarboxamide (II) by means of p-toluenesulfonic acid in toluene at reflux gives the ethyl ester of the acid (S) -7-Chloro-2- (2,2-dimethylcyclopropanecarboxamido) -2heptenoic (III), which is hydrolyzed in aqueous NaOH to give the corresponding carboxylic acid (IV). Finally, this compound is condensed with (R) -cysteine (V) by means of NaOH in water to obtain the desired cilastatin,

25 followed by isomerization at pH 3.0. The procedure followed in this example is represented below: EP0072014A1 claims an antibacterial composition comprising a penem derivative with a dipeptidase inhibitor (cilastatin). This patent publication describes the process for the preparation of acidic cilastatin and its conversion into the sodium salt in example-19A.

WO 03/018544 claims a process for the purification of cilastatin, which comprises contacting a crude cilastatin solution with a non-ionic adsorbent resin and recovering the pure cilastatin from a solution thereof. This publication also claims a process for isomerization of cilastatin by heating a cilastatin solution containing the corresponding E-isomer at a pH of about 0.5 to 1.5. This invention is not suitable with factory views because it includes column chromatography.

US 2004/0152780 claims a process for the preparation of pure sodium cilastatin in an amorphous form comprising recovering the sodium cilastatin from a solution thereof containing an organic solvent, a homogeneous mixture of organic solvents, or a homogeneous mixture of organic solvents and water, by precipitation in the solvent. According to this patent, pure sodium cilastatin was recovered in amorphous form from the solution of sodium cilastatin in a solvent (in which sodium cilastatin was soluble) by adding an anti-solvent (in which sodium cilastatin was insoluble).

WO 2006/022511 claims a process for preparing sodium cilastatin through the amine salt of cilastatin, and also said patent claims the ammonium salt of cilastatin. However, EP 0 048 301 page 2; line 33-37 & US 4,616,038 col 36; 40-44 anticipates the claim of said publication. This patent also uses column chromatography to separate sodium chloride.

However, taking into account the commercial importance of cilastatin sodium and imipenem, there is still a need for a convenient procedure. Therefore, research has focused on finding alternative procedures and a procedure that eliminates the aforementioned problems associated with the previous procedures has been achieved.

Object of the invention

The main objective of the present invention is to provide a commercial process for the preparation of cilastatin.

Another objective is to provide a procedure that avoids the use of chromatography and provides direct isolation of cilastatin.

Compendium of the invention

The present invention provides an improved process for the preparation of pure acidic cilastatin of the formula (I), which comprises the steps of:

i) condensing 7-chloro-2 - [[(1S) -2,2-dimethylcyclopropane] carboxamide] -2-heptenoic acid of the formula

(I) with L-cysteine or L-cysteine hydrochloride monohydrate or L-cysteine hydrobromide monohydrate, in the presence of a base and an alcoholic solvent or aqueous alcoholic solvent,

ii) optionally separating the inorganic salt, for example NaCl or KCl, by filtration and concentrating the filtrate,

iii) optionally add water,

iv) adjust the pH from 2.0 to 4.0,

v) extracting the acidic cilastatin with C4-C8 alcohol, for example selected from the group comprising n-butanol, cyclohexanol, and

vi) isolate acid cilastatin.

Detailed description of the invention

In one embodiment of the present invention, the base used in step (i) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate and the like, and the alcoholic solvent used in step (i) is selected from methanol, ethanol, isopropanol and the like. It has been found that condensation of the compound of formula (II) with L-cysteine in the alcoholic solvent medium gives cilastatin in pure form, where impurity formation is negligible.

In yet another embodiment of the present invention, the L-cysteine used in step (i) is in the form of L-cysteine hydrochloride monohydrate or L-cysteine hydrobromide monohydrate.

In another embodiment of the present invention, the pH of the reaction mass is adjusted from 2.0 to 4.0 using hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid and the like.

In another aspect the inorganic salts such as NaCl, KCl are filtered from the reaction mass, if the condensation takes place in an alcoholic solvent medium, before the pH adjustment.

In a further embodiment of the present invention, cilastatin can be extracted in solvents such as C4-C8 alcohol selected from the group comprising n-butanol, cyclohexanol, followed by isolation of the acidic cilastatin from the resulting layer. In another aspect the acid cilastatin is isolated from the C4-C8 alcohol layer by reducing the volume of the layer followed by filtration of the precipitated acid cilastatin, or by evaporating the layer followed by crystallization of the acid cilastatin from the mixture of water and water miscible solvent.

In yet another embodiment of the present invention, the cilastatin obtained according to the present invention can optionally be subjected to an isomerization process by methods known in the prior art.

In yet another embodiment of the present invention, the starting material 7-chloro-2 - [[(1S) -2,2-dimethylcyclopropane] carboxamide] -2-heptenoic acid of the formula (II) is prepared using the available process of prior art

In yet another embodiment of this invention, the solvent used for the dissolution of acidic cilastatin is selected from ethanol, isopropanol, n-butanol, denatured alcohol, acetone, THF, acetonitrile, DMF and the like or mixtures thereof.

The present invention is illustrated by the following examples, which are provided for illustration only and should not be considered as limiting the scope of the invention.

Example 1

Acid Cilastatin Preparation:

To the solution of sodium hydroxide (88 g) in methanol (1500 ml) was added Z-7-chloro-2 - [[(1 S) -2,2-dimethylcyclopropane] carboxamide] -2-heptenoic acid and stirred to dissolve. L-cysteine monohydrate hydrochloride (97 g) was added to the resulting clear solution and the resulting suspension was stirred at a temperature of 60 to 65 ° C until the disappearance of Z-7-chloro-2 [[((1S) -2] , 2-dimethylcyclopropane] carboxamide] -2-heptenoic. After completion of the reaction, the pH, the insoluble salts were filtered. The filtrate was removed by vacuum distillation. The residue was dissolved in water (500 ml) and washed with dichloromethane (500 ml). The pH of the aqueous layer was adjusted from 3 to 4 from the original pH in the range of 5.5, and with n-butanol (500 ml). The butanol layer was washed with water and distilled. The residue was dissolved in water (100 ml) and acetonitrile (1500 ml) was added at 50 ° C and then refluxed at 80 ° C for one hour. The precipitated acidic cilastatin was filtered and washed with acetonitrile (100 ml). The raw wet cake (60 g) was refluxed with a mixture of acetonitrile water (9: 1,1500 ml), and cooled to give 60 g of pure acidic cilastatin with a purity of 99.5%.

Example 2

Acid Cilastatin Preparation:

To the solution of sodium hydroxide (88 g) in methanol (1500 ml) was added Z-7-chloro-2 [[(1S) -2,2-dimethylcyclopropane] carboxamide] -2-heptenoic acid and stirred to dissolve. L-cysteine monohydrate hydrochloride (97 g) was added to the resulting clear solution and the resulting suspension was stirred at a temperature of 60 to 65 ° C until the disappearance of Z-7-chloro-2 [[((1S) -2] , 2-dimethylcyclopropane] carboxamide] -2-heptenoic. The pH of the reaction mass was adjusted to 7.0 with concentrated HCl and the insoluble salts were filtered. The filtrate was removed by vacuum distillation. The residue was dissolved in water (500 ml) and washed with dichloromethane (500 ml). The pH of the aqueous layer was adjusted from 3 to 4 from the original pH in the range of 5.5, and with n-butanol (500 ml). The butanol layer was washed with water and distilled to 50% of the original volume and stirred at 25 ° C. The precipitated acid cilastatin was filtered and washed with n-butanol (100 ml) followed by acetone to give 60 g of pure acid cilastatin with a purity of 99.7%.

Claims (3)

1. An improved process for the preparation of acidic cilastatin of the formula (I), comprising the steps of: i) condensing 7-chloro-2 - [[(1S) -2,2-dimethylcyclopropane] carboxamide] -2-heptenoic acid of the formula (II) with L-cysteine or L-cysteine hydrochloride monohydrate or L-cysteine hydrobromide monohydrate, in the presence of a base and an alcoholic solvent or aqueous alcoholic solvent, 10 ii) optionally separating the inorganic salt by filtration and concentrating the filtrate, iii) optionally add water, iv) adjust the pH from 2.0 to 4.0, v) extract the acidic cilastatin with C4-C8 alcohol, and vi) isolate the acidic cilastatin.

2. A process according to claim 1, wherein the alcohol solvent used in step (i) is selected from methanol, ethanol or isopropanol, and the base used in step (i) is selected from sodium hydroxide, hydroxide of potassium, or sodium carbonate.

3. A process according to claim 1, wherein the extraction of acidic cilastatin in step (v) is carried out using C4-C8 alcohol selected from n-butanol or cyclohexanol.

A method according to claim 1, wherein the isolation of acidic cilastatin is carried out by reducing the C4-C8 alcohol to half of its original volume, followed by filtration.

5. A process according to claim 1, wherein the isolation of acidic cilastatin is carried out by concentrating the C4-C8 alcohol layer, followed by crystallization of the solid.